In the research set forth in this proposal, it is our aim to undertake syntheses of a wide variety of new cocaine analogues. From a combination of molecular modeling studies, chemical synthesis, and receptor binding/functional studies, including binding to both the membrane DA and 5-HT carriers, inhibition of 3H-DA and 3H-5-HT uptake, and the use of intact preparations to detect a functional antagonism, we hope to gather information pertinent to: (a) deciphering the particular conformation which cocaine assumes at some of the receptors with which it interacts; and (b) ascertaining the extent to which certain structural changes can alter cocaine's functional properties. From such fundamental neurochemical investigations it is our intent to create a database of 3-D structural-functional information which may guide us in the eventual design of agents which: (1) may be used to counter some of the adverse side effects of cocaine; or (2) may lead to the development of a "cocaine antagonist" for use in maintaining patients in treatment programs. Additionally, it is conceivable that these basic chemical/pharmacological studies could lead to the discovery of a new class of non-addictive CNS stimulants for use in countering depressive disorders.